Despite major advances toward understanding the pathophysiology of gram negative infection, sepsis remains a significant problem in Medicine, annually affecting 750,000 patients and causing over 200,000 deaths. The sepsis syndrome results from exposure to bacterial lipopolysaccharide (LPS) which triggers the host innate immune response, including the activation of specific preprogrammed cellular responses. This branch of the mammalian immune system includes the acute phase response, and is designed to rapidly identify and neutralize invading pathogens while protecting the host from injury. As such, the innate immune response is largely predicated on the recognition of pathogen-associated molecular patterns via pattern recognition receptors expressed on the surface of various cells, including macrophages and monocytes. While leukocytes clearly play a sentinel role in the early response to microbial infection, efforts in our laboratory have focused on understanding the molecular basis for the "lipemia of sepsis," a facet of the acute phase response involving the increased production of triglyceride (TG)-rich lipoproteins by the liver. We hypothesize that TG-rich lipoproteins, i.e. chylomicrons (CM) and VLDL, in addition to their well-known role in lipid metabolism, are also components of the host innate immune response to infection. We have previously demonstrated that CM and VLDL can bind and neutralize LPS and thus protect against endotoxic shock and death in rodent models of sepsis. We also found that the internalization of CM-bound LPS rendered hepatocytes refractory to the stimulatory effect of pro-inflammatory cytokines, a process we termed cytokine tolerance. Additional preliminary data have led us to the hypothesis that CM-bound LPS selectively inhibits the TNF signal transduction pathway in hepatocytes. This proposal is focused on not only delineating the molecular mechanism behind this observed response, but also on examining how CM-bound LPS may effectively regulate the acute phase response in vivo. Consequently, we will delineate an intriguing sequence of events whereby a foreign molecule (LPS) serves to both trigger and regulate a preprogrammed cellular stress response. Contrary to most therapeutic strategies to combat sepsis, study of this novel observation may yield clinically relevant insight into mechanisms for manipulating the response of target cells and organs to pro-inflammatory stimuli.